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  • Review Article
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The SIRP family of receptors and immune regulation

Nature Reviews Immunology volume 6, pages 457–464 (2006)Cite this article

Key Points

  • The signal-regulatory proteins (SIRPs) can be classed as paired receptors, the most well known of which include the killer-cell immunoglobulin-like receptors, which are expressed by natural killer cells.

  • The SIRP family contains activating, inhibitory and non-signalling members, which have closely related extracellular regions but distinct cytoplasmic tails. They are expressed mainly by myeloid cells and are therefore thought to have a role in immune regulation.

  • Two types of ligand for the inhibitory member, SIRPα, have been identified: the widely expressed cell-surface protein CD47 and surfactant protein A.

  • A third SIRP-family member, SIRPγ, transmits neither activating nor inhibitory signals even though it binds CD47.

  • Like other paired receptors, the SIRPs show evidence of rapid evolution with considerable species differences and polymorphisms.

  • Factors such as ligand availability, binding affinity, protein mobility and expression levels are likely to affect their function in vivo.

Abstract

The immune system must be highly regulated to obtain optimal immune responses for the elimination of pathogens without causing undue side effects. This tight regulation involves complex interactions between membrane proteins on leukocytes. Members of the signal-regulatory protein (SIRP) family, which are expressed mainly by myeloid cells, provide one example of these regulatory membrane proteins. There are three SIRP-family genes that encode proteins that have similar extracellular regions but different signalling potentials, and are therefore known as 'paired receptors'. In this Review, we describe recent studies defining the ligands of the SIRP-family members, with particular emphasis on relating the molecular interactions of these proteins to their role in immune-cell regulation.

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Figure 1: Interactions of members of the signal-regulatory protein family.
Figure 2: The topology of interactions between an antigen-presenting cell and a T cell.

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  1. Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK

    A. Neil Barclay & Marion H. Brown

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Glossary

Immunological synapse

A region that can form between two cells of the immune system that are in close contact, so named because of its similarities to the synapses that occur in the nervous system. The immunological synapse originally referred to the interaction between a T cell and an antigen-presenting cell, but it is now known to form between other types of immune cell, for example, between dendritic cells and natural killer cells. It involves adhesion molecules, as well as antigen receptors and cytokine receptors.

Immunoreceptor tyrosine-based inhibitory motif

(ITIM). A short peptide motif that contains tyrosine residues and is found in the cytoplasmic tails of several inhibitory receptors. The prototype six-amino-acid ITIM sequence is (I/V/L/S)XYXX(L/V), with X denoting any amino acid. Ligand-induced clustering of these inhibitory receptors results in tyrosine phosphorylation, often by SRC-family protein tyrosine kinases, and this provides a docking site for the recruitment of cytoplasmic phosphatases that have an SRC homology 2 (SH2) domain.

Immunoglobulin superfamily domain

(IgSF domain). This domain type shows sequence similarity to domains present in immunoglobulins and is the most common domain type of leukocyte surface proteins.

Domain

Region of a protein that forms a discrete fold. The extracellular regions of leukocyte surface proteins contain several common domain types, such as immunoglobulin superfamily and C-type lectin domains.

Immunoreceptor tyrosine-based activation motif

(ITAM). A short peptide motif containing tyrosine residues that is found in the cytoplasmic tails of several signalling molecules. The amino-acid sequence of an ITAM is (D/E)XXYXX(L/I)X6–8YXX(L/I), with X denoting any amino acid. It is tyrosine phosphorylated after engagement of the ligand-binding subunits, which triggers a cascade of intracellular events that results in cellular activation.

Polymorphic

In population genetics, this term refers to genes that, in a population, have many alleles.

Collectin

C-type lectins that have a collagen-like domain are known as collectins. One group of collectins, the secreted lectins, consists of mannose-binding lectin (MBL), bovine conglutinin and collectin-43 (CL43) in blood and the two mucosal-associated proteins surfactant protein A (SP-A) and SP-D. The other group of collectins consists of the newly discovered, non-secreted-type collectin liver 1 (CLL1) and membrane-type collectin placenta 1 (CLP1).

Erythropoiesis

The differentiation process leading from a committed erythroid precursor to the production of mature red blood cells (erythrocytes).

Thrombocytopaenia

A reduced number of circulating platelets, owing to either the failure of production from bone-marrow megakaryocytes or increased clearance from the circulation, predominantly in the spleen.

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Barclay, A., Brown, M. The SIRP family of receptors and immune regulation. Nat Rev Immunol 6, 457–464 (2006). https://doi.org/10.1038/nri1859

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